Substituted gamma-2-thenoyl-butyric acid



Patented Feb. 14, 1950 SUBSTITUTED GAMMA-Z-THENOYL- BUTYRIC ACID DanielHetfieldTerry, Plainfield. N=..J., andCarlton Webster Croco, Swarthmore,Pa, assignqrs to E. I. du' Pont de Nemoursd: Company, Wllnr'nington,Del., a corporation of Delaware N Drawing.

4Claims. 1

This invention relates to novel organic com.- pounds.

It is an object of this invention, to. produce. novel organic compoundsuseful as intermediates for the synthesis of pharmaceuticals. A, furtherobject is to produce novel organic. compounds particularly adapted foruse as intermediates in the synthesis of biotin and related compounds.Other and further important objects of this in vention will becomeapparent from thefollowing description.

The novel compoundsof. this invention may. be, expressed by the generalformula t t Y 5 2 -o o-omcmomooon.

s wherein X designates a; radical such as nitro, amino or acylamino,while. Y stands for hydrogen or halogen when X is nitro, or simply. forhydro- Application December 11 1946, Serial No. 7151.618

gen when X is amino oracylaminm The fundamental compound from which theradical lb t o 0-0 O-OHCH2CH2.COOH- is derived is commonly designated asgamma-2- thenoyl-butyric acid; and in accordance therewith. the newcompounds of this invention may be designated as 4-nitro, 4-amino or4-acyl-. amino-gamma-Z-thenoyl-butyric acids, and the corresponding5-halogenoderivatives. Alternatively, the may be expressed by thegeneral formula R-CQCH2CH2CH2 .COOH' wherein Rv is a thienylv radical.attached; to the CO group through the. 2-position and. carrying-I 2 beconverted into. an. optional 4.acylamino de-.. rivative such. asacetamid benzoylaminm. car boethoxy-amino and. the like; If. the,ii-nitro. compound initially. prepared contains. a, halogen.

. atom in, the 5-position. the samebecpmes elimi;-.

nated in. the reduction step ..v

Without limiting. our invention the following examples are, given. toillustrate. our preferred, mode of. operation. Parts, mentioned; are,by.- weight.

Example 1 .-=-Gamma- 64-nitrc-2ethenoyvabutyr to. acid 5.0.. par s, ofgamma-z-then i-hntyric a d were dissolved in 460 parts of 96%,sulfuricacid at 35 C. while agitating. parts ofa mixed acid (containing33% nitric acid and 67% sulfuricacid) were addedtothe above; solutionover a. period. of 15. minutes. at. 3-5? C. while. agitatin The reactionmass was then agitated; at 3-5 C. for 15 minutes longer, andpoured1intm1500parts= of ice and water. The precipitate was filtered offand washed acid-free with ice water. After several recrystallizationsrfrom ethyl. alcolrml,v the; product, gamma (4-nitro-2-thenoyll -bntyricacid was obtained as pale yellowplatesymeltingz at lei-146 C...

t Calculatedfor Anal? notoimsodcmte-oon Percent 5 Percent N- v 5.85;5.76. N02 1s. 84 18. 9,0.

The gamma-z-thenoylsbutyric acid employed inthe above example wasprepared by themethod; described. in J. Biol. Chem. .45,, 431-492.619,42) from thiophene and glutaric anhydride, using, A1013; as.catalyst.

Example 2.Gamma- (5-bromo-4-nitro-2-thenoyl) -butyric acidGannna-(B-bromo-Z-thenoyl) -butyric acid was prepared by the method usedhereinabove to make gamma-(2-thenoy1)-butyric acid, except that we usedZ-bromo-thiophene in place of thiophene.

The gamma (5 bromo-Z-thenoyD-butyric acid was then nitrated in a mannersimilar to that set forth above in Example 1, again using mixed acid at3 to 5 C. and precipitating the product with ice Water. The resultinggamma- (5-bromo-4-nitro-2-thenoyl)-butyric acid had a melting point of152.6-155.4 C. after several recrystallizations from alcohol.

Example 3. Gamma-(4-carboethozry-amino-2- thenoy'l) -butyric acid 48.6parts of gamma-(4-nitro-2-thenoyl)- butyric acid, as obtained in Example1, were added to a solution of 150 parts of stannous chloride in 170parts of concentrated hydrochloric acid (37%) at -25 C. over a period offifteen minutes while agitating, and then agitated for one hour longer.The flask was then flushed out with hydrogen to remove the air. 800parts of sodium hydroxide solution were slowly added at 20-25 C. whileagitating. Then 45 parts of ethyl chlorocarbonate were added slowly andthe temperature was allowed to rise to 34 .C. and held at 32-34" C. forone hour. Concentrated hydrochloric acid was added slowly until thesolution was acid to Congo red test paper at 25-30 C. The precipitatewas filtered off and washed with water. The wet cake was dissolved insodium carbonate solution and filtered. The filtrate was made acid toCongo red test paper with hydrochloric acid. The precipitate wasfiltered off and washed well with water and dried. Afterrecrystallization from ethyl alcohol, .the melting range of the whiteproduct, which presumably was gamma- (4-carboethoxy .amino-2-thenoyl)-butyric acid,

was 156-159 C.

- Calculated for Analysls Fmmd CzHsO.CONH.C4H2S.CO.C3H6.COOH

Percent Percent No, Nil 0 N- 4.80 4. 92

Example 4.-Ga.mma (4 carboethomy-amino-Z- thenoyD-buiyric acid fromgamma-(5-bromo- 4-nitro-2-thenoyl) -b'utyric acid preferred embodimentsof this invention, it will be clear that many modifications andequivalents are possible without departing from the spirit of thisinvention. Thus, in lieu of sulfuric acid in the nitration step othersolvents commonly used for nitrations may be employed, for instanceglacial acetic acid. The temperature and time of treatment may be variedwithin wide limits.

In lieu of the bromo derivatives employed in the above examples, other5-halogeno derivatives may be employed, for instance the 5-chloro or5-iodo compounds. All these halogen derivatives may be prepared from thecorresponding 2- halogen thiopene by the method indicated in Example 2above, while the preparation of the 2- halogen thiophene itself mayfollow in general the procedure employed with respect to a series ofanalogous compounds in copending application of Terry and Croco, SerialNo. 637,480, filed December 27, 1945, now abandoned; in other words, byacting with the corresponding free halogen (e. g. chlorine, bromine oriodine) upon thiophene in a suitable solvent, such as glacial aceticacid.

In the reduction of the 4-nitro compounds above to the correspondingamino compounds, the stannous chloride specified may be replaced byother customary reducin agents, for instance iron.

Also other acylating agents may be used in place ofethyl-chloro-carbonate, for instance acetic anhydride, acetyl chloride,benzoyl chloride, etc.

The new compounds are useful in the preparation of pharmaceuticalproducts, containing the thiophene nucleus, for instance biotin and alsonew biotin-like compounds not found in nature.

We claim as our invention:

1. A compound of the general formula wherein R is a thienyl radicalselected from the group consisting of 4-nitro-thienyl, 4-nitro-5-halogeno-thienyl, 4-amino-thienyl, and 4-acylamino-thienyl, the CO groupof the above formula being attached to said thienyl radical in the2-position.

2. Gamma-(4-nitro-2-thenoyl) -butyric acid. 3. Gamma (5 -bromo 4nitro-2-thenoyl) butyric acid.

4. Gamma (4 acylamino-Z-thenoyl) -butyric acid.

DANIEL HE'IFIELD TERRY. CARLTON WEBSTER CROCO.

REFERENCES CITED The following references are of record in the file ofthis patent:

Steinkopf, Die Chemie Des 'I'hiophens, 1941, Edwards Lithoprint 1944,pages 71, '74, and 84.

1. A COMPOUND OF THE GENERAL FORMULA